PROJECT SUMMARY Heavy alcohol (ETOH) use affects both the brain and liver. ETOH effects on the brain may be exacerbated by associated hepatic and metabolic disturbances, including insulin resistance, oxidative stress, and mitochondrial dysfunction. HIV also affects the brain and has similar associated comorbidities. The proposed study will investigate effects of ETOH consumption on HIV-associated brain dysfunction, incorporating state-of-the-art brain imaging methods along with clinical and laboratory methods to assess the interactive effects of ETOH consumption on HIV-associated brain dysfunction. There are two broad objectives. The first is to continue an ongoing line of research, extending current findings by incorporating functional neuroimaging (FMRI) approaches, along with additional magnetic resonance spectroscopy (MRS) methods that will enable us to delineate both functional and cerebral metabolic disturbances affecting specific functional brain systems that are associated with the interaction of ETOH and HIV, as well as alterations in functional connectivity within and between these systems. The second objective is to examine the extent to which reductions in ETOH consumption among heavy drinkers with HIV infection that result from a motivational intervention lead to improvements in these functional and metabolic neuroimaging measures, as well as neurocognitive performance. This intervention, which is the focus of ARCH Research Component 2, has been shown to be effective in reducing ETOH consumption by 50% over a 6-month follow-up whereas HIV care as usual was associated with no changes in drinking. Recent data from ARCH Research Component 1 indicate that HIV- infected patients with heavy ETOH consumption have FMRI abnormalities and exhibit alterations on other neuroimaging measures compared to moderate drinkers and people who do not drink at all. Moderate drinkers did not differ from non-drinkers. Abnormalities of cerebral white matter integrity on diffusion tensor imaging (DTI) were also found among heavy ETOH users. These effects were associated with current ETOH consumption, but not lifetime history, suggesting that ETOH-associated brain abnormalities in people with HIV may be reversible when there has been a significant reduction in ETOH use. Neuroimaging, laboratory, and neurocognitive assessment will be conducted at baseline and at 6-months following randomization to motivational intervention (MI) or assessment only. The findings from this study will provide important information on how heavy ETOH and HIV interact to affect the brain functional responsiveness, and the extent of improvement that might be gained by reducing heavy ETOH use. The study will also likely yield new neuroimaging metrics of functional, metabolic, and structural brain dysfunction, potentially leading to their use as neuroimaging biomarkers for the assessing patients with HIV and other diseases that affect the brain.